WO2010084507A2

WO2010084507A2 - Process for the preparation of n-methyl-2-[3-(1-methyl-4-piperidyl)-1h-indol-5-yl]-ethanesulfonamide and its acid addition salts

Info

Publication number: WO2010084507A2
Application number: PCT/IN2009/000683
Authority: WO
Inventors: Bhavna Nikhil Tailor; Arun Gulabsingh Yadav; Rajeev Budhdev Rehani; Rajamannar Thennati
Original assignee: Sun Pharmaceutical Industries Ltd.
Priority date: 2008-07-15
Filing date: 2009-07-14
Publication date: 2010-07-29
Also published as: WO2010084507A3

Abstract

A process for the preparation of compound of formula (1) or acid addition salt thereof is disclosed.

Description

PROCESS FOR THE PREPARATION OF N-METH YL-2-[3-(l -METHYL-4- PIPERID YL)-m-INDOL-5-YL]-ETHANESULFONAMIDE AND ITS ACID ADDITION SALTS

FIELD OF INVENTION

The present invention relates to an improved process for preparing N-methyl-2-[3-(l- methyl-4-piperidyl)-lH-indol-5-yl]-ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1

The compound of formula 1, commonly known as Naratriptan, is a selective 5-HT₁ receptor agonist, which binds to the 5 -HTl receptors located on the intracranial blood vessels with high affinity and produces vasoconstriction.

BACKGROUND OF THE INVENTION United States patent no. 4,997,841 (referred to as '841 hereinafter) describes naratriptan and related compounds and salts thereof as being useful in the treatment of migraine, cluster headache and headache associated with vascular disorders. The hydrochloride salt of naratriptan is an approved drug which is marketed in several countries worldwide for the acute treatment of migraine attacks in adults. In United States it is sold under the trade name AMERGE^® (Glaxo Smithkline Beecham).

The '841 patent discloses process for preparing naratriptan and related compounds. One of the processes for preparing naratriptan involves reaction of 2-(4-Hydrazino-phenyl)- ethanesulfonic acid methylamide, a compound of formula 2, with (l-Methyl-piperidin-4- yl)-acetaldehyde, a compound of formula 3. (See Scheme I).

formula 2 formula 3 formula 1

Scheme I

This reaction suffers from several limitations, such as:

• It requires a prolonged reaction time of about 2 days.

• The intermediate hydrazone product of the reaction of compound of formula 2 with compound of formula 3, is isolated as a crude oil and requires addition of further quantities of Lewis acid such as polyphosphate ester for its further conversion to naratriptan.

• The process involves use of flash chromatography for the purification of naratriptan, which is not feasible for large scale production.

• The yields obtained are poor (about 7%).

European Patent Application No. 0581538 (referred to as EP'538 hereinafter) discloses a method of preparing (l-Methyl-piperidin-4-yl)-acetaldehyde, the compound of formula 3, starting from 1 -methyl -piperidin-4-one, a compound of formula 4. The process involves four steps as outlined in Scheme II and are as follows:

1. Reaction of l-methyl-piperidin-4-one, a compound of formula 4, with methyl diethyl phosphonoacetate, a compound of formula 5, in presence of sodium hydride and tetrahydrofuran (THF) to yield l-methyl-piperidin^-ylidene-acetic acid methyl ester, a compound of formula 6. 2. Reduction of l-methyl-piperidin-4-ylidene-acetic acid methyl ester, a compound of formula 6 using Pd/C, hydrogen at high atmospheric pressure (40psi) and in acidic conditions to yield (1 -methyl piperidin-4-yl) acetic acid methyl ester, a compound of formula 7. 3. Reduction of (l-methyl-piperidin-4-yl) acetic acid methyl ester, a compound of formula 7, to 2(l-methyl-piperidin-4-yl)-ethanol, a compound of formula 8, using DIBAL-H (Diisobutyl aluminium hydride) at sub-zero temperature of -35 ⁰C.

4. Oxidation of 2-(l-methyl-piperidin-4-yl)-ethanol, a compound of formula 8, to (1- Methyl-piperidin-4-yl)-acetaldehyde, a compound of formula 3, using DMSO and oxalyl chloride

form ula 4 form u la 5 form u la 6 form u Ia 7

D IBAL -35

D M SO , oxalyl chloride

form u la 3 form u la 8

Schem e Il

In another reference, Borne et al. J. Het. Chem., 869, 1972, l-methyl-piperidin-4- ylidene-acetic acid ethyl ester, the compound of formula 6, is prepared in a manner similar to that in '538 patent using monoglyme as a solvent.

These prior art process for preparing compound of formula 3 have a number of limitations, such as: • The reaction in step 1 involves use of hazardous and highly reactive base such as sodium hydride, which is very sensitive towards moisture and warrants absolute anhydrous conditions.

• The reaction in step 2 involves reduction using elevated pressure and acidic conditions and step 3 employs sub-zero temperatures upto -35⁰C for the reduction of the ester compound of Formula 7.

• The overall yield of acetaldehyde intermediate, a compound of formula 3, is only about 6-7%.

These limitations in combination with the high cost of reagents and solvents, seriously jeopardize the industrial applicability of the process.

Therefore, there is a strong need for a commercially viable process for preparing N- methyl-2-[3-(l-methyl-4-piperidinyl)-lH-indol-5yl]-ethanesulfonamide, a compound of formula 1, or acid addition salt thereof, which uses safer reagents, milder conditions of temperature, produces high yield of quality material and is suitable for large scale production. The commercial feasibility of such a process for preparing compound of formula 1 is highly dependent on an industrially viable and economical method for preparing (l-Methyl-piperidin-4-yl)-acetaldehyde, the compound of formula 3, which is a key intermediate in the synthesis of compound of formula 1 , naratriptan.

The present invention provides a process for preparation of N-methyl-2-[3-(l-methyl-4- piperidyl)-lH-indol-5yl]-ethanesulfonamide, the compound of formula 1, or acid addition salt thereof by using safer reagents and milder conditions of temperature to produce high yield of quality material and is suitable for large scale production.

The present invention also provides a process for the preparation of (1-Methyl-piperidin- 4-yl)-acetaldehyde, a compound of formula 3.

The process of the present invention for preparing compound of formula 3 is advantageous as step 1 is carried out using innocuous base like potassium hydroxide in place of hazardous base like sodium hydride and obviates the need of absolute anhydrous conditions. Further the hydrogenation of the olefinic ester in the second step requires atmospheric pressure or very low pressure of upto 1 Kg/cm² as compared to high atmospheric pressure of 40psi used by the EP'538 process. Further, the hydrogenation is carried out under non-acid conditions as compared to use of mineral acid by EP'538 process. Also, the reduction of the ester in the third step is carried out at temperatures in the range of -5⁰C to 1O⁰C as compared to the drastic sub-zero temperature of -35⁰C required in the EP'538 process. The present invention provides 6 times higher yield of the compound of formula 3 as compared to the process disclosed in EP'838 patent. Further, in one aspect the method of preparation of compound of formula 3 involves lesser number of steps as compared to the process of prior art. Thus the process of the present invention uses safer reagents and milder conditions of temperature.

The reaction of compound of formula 2 with compound of formula 3 to give compound of formula 1 , is a single pot reaction which does not require isolation of the intermediate hydrazone product and addition of any further quantities of acid like polyphosphates, which is an added advantage over the prior known process for the said step. Further, the process requires considerably lesser time as compared to the '841 process which requires a time period of 2 days. A substantially higher yield of 66% is obtained in this step as compared to 7% yield obtained in the '841 patent. Further the process of producing compound of formula 1 inherently obviates formation of most of the impurities listed in USP monograph for compound of formula 1.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing N-methyl-2-[3-(l-methyl-4- piperidyl)-lH-indol-5-yl]- ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1 comprising the steps of :

(a) reacting a compound of formula 7 with sodium diisobutyl-t-butoxyaluminium hydride reagent in presence of an alkali metal alkoxide to obtain a compound of formula 3,

Formula 7 Formula 3 wherein R₁ is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

(b) reacting the compound of formula 3, with a compound of formula 2

Formula 2 to obtain a compound of formula 1 and optionally converting it to an acid addition salt. The present invention provides a process for preparing N-methyl-2-[3-(l-methyl-4- piperidyl)-lH-indol-5-yl]-ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1 comprising the steps of :

(a) reacting the compound of formula 7 with sodium bis(2-methoxyethoxy) aluminum hydride to obtain a compound of formula 8

Formula 7 Formula 8 wherein Ri is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

(b) reacting the compound of formula 8, with dimethyl sulfoxide and oxalyl chloride in presence of an organic base to obtain a compound of formula 3, and

Formula 3

(c) reacting the compound of formula 3 with a compound of formula 2

Formula 2 to obtain a compound of formula 1 and optionally converting it to an acid addition salt.

The present invention provides a process for preparing the compound of formula 7

Formula 7 comprising the steps of : (a) reacting a compound of formula 4

Formula 4 with a compound of formula 5

Formula 5 in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain an olefinic ester, a compound of formula 6

Formula 6 wherein each R₁ in Formula 5 and Formula 6 is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; and

(b) hydrogenating the compound of formula 6 obtained in step (a) above, to obtain a compound of formula 7, wherein R₁ has the meaning as defined above.

The present invention provides a process for preparing, a compound of formula 3

Formula 7 Formula 3 comprising reacting a compound of formula 7, wherein R₁ is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, with sodium diisobutyl-t- butoxyaluminium hydride reagent in presence of an alkali metal alkoxide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of compound of formula 1 or acid addition salt thereof

Formula 1

In one embodiment the compound of formula 1 or salt thereof, is prepared by a process comprising the steps of:

(a) reacting a compound of formula 7 with sodium diisobutyl-t-butoxyaluminium hydride reagent in presence of an alkali metal alkoxide to obtain a compound of formula 3;

Formula 7 Formula 3 wherein R₁ is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. (b) reacting the compound of formula 3 with a compound of formula 2

The reaction of the saturated ester derivative, compound of formula 7 with sodium diisobutyW-butoxyaluminium hydride reagent in presence of an alkali metal alkoxide to obtain l-methyl-piperidin-4-yl acetaldehyde compound of formula 3, may be carried out in presence of a suitable organic solvent.

The alkali metal alkoxide may be selected from sodium t-butoxide, potassium-t-butoxide 5 and the like, sodiunW-butoxide being the prefered alkali metal alkoxide.

A suitable organic solvent for the reaction may be selected from the group consisting of ethers or aromatic and/or aliphatic hydrocarbons. Suitable ether may be diethylether, diphenylether, tetrahydrofuran (THF). An aromatic and/or aliphatic hydrocarbon solvent 10 may be toluene, cyclohexane, hexane, heptane and the likes or mixtures thereof. The prefered organic solvent is THF. The reaction can be carried out at a temperature range of -20⁰C to 1O⁰C, preferably in the temperature range of -5⁰C to 0⁰C.

The (l-Methyl-piperidin-4-yl) acetaldehyde, compound of formula 3, is converted to N- 15 methyl-2-[3-(l-methyl-4-piperidyl)-l//-indol-5-yl]-ethanesulfonamide, compound of formula 1 or its salt. This process involves the reaction of a hydrazine compound of formula 2 with l-methyl-piperidin-4-yl acetaldehyde, compound of formula 3. The reaction may be carried out in acid catalysts in presence of an organic solvent.

20 Suitable acid catalyst for the reaction may be selected from mineral acids like hydrochloric acid, sulfuric acid, polyphosphoric acid, or lewis acid like zinc chloride, aluminium chloride or organic acids like acetic acid and the like or mixtures thereof.

A suitable solvent can be selected from alkanols like methanol, ethanol, isopropanol etc.

25. Preferably, the reaction is carried out using hydrochloric acid as the acid catalysts and ethanol as the solvent. Further, the reaction may be carried out at a temperature from 50⁰C to 80⁰C for a period of 10-15 hours, preferably between 70⁰C to 80⁰C for a period of 12- 14 hours. According to a preferred aspect of the present invention the reaction is advantageously carried out in a single pot without isolating the intermediate hydrazone

30 product at pH <2, under non-anhydrous conditions. The reaction may yield compound of formula 1 in the form of base or salt. Alternatively, the compound of formula 1 may be converted to its salt. Since the compound of formula 1 possess a basic center (Tertiary amine) in its structure, it can form acid addition salts. The acid addition salts may be selected from mineral acid salts e.g. hydrochloride, hydrobromide, sulfate, organic acid salts e.g. citrate succinate, maleate, fumarate, malate, tartarate, myristate, pamoate, etc., sulfonates e.g. methanesulfonates, benzenesulfonates, toluensulfonates and other salts which are customarily employed in pharmaceutical field in connection with the basic compounds. Preferably the salt is hydrochloride salt. The process of preparation of such acid addition salt of a basic drug is well known in the art.

In another embodiment the present invention provides a process for preparing N-methyl-2- [3-(l-methyl-4-piperidyl)-lH-indol-5-yl]-ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1 comprising the steps of :

Formula 7 Formula 8 wherein Ri is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; (b) reacting the compound of formula 8, with dimethyl sulfoxide and oxalyl chloride in presence of an organic base to obtain a compound of formula 3, and

Formula 3 (c) reacting the compound of formula 3 with a compound of formula 2

The reaction of the saturated ester derivative of formula 7 with sodium bis(2- methoxyethoxy) aluminum hydride to obtain 2-(l-methyl-piperidin-4-yl)-ethanol, compound of formula 8, may be carried out at a temperature ranging from subzero to 4O⁰C, preferably from -5 ⁰C to 1O⁰C. The hydride, sodium bis(2-methoxyethoxy) aluminum hydride is commonly known as vitride. The reaction may be carried out in presence of an organic solvent selected from the group consisting of aromatic hydrocarbons or ethers. The aromatic hydrocarbon may be selected from toluene, xylene and the like. Preferably the organic solvent is toluene.

The 2-(l-methyl-piperidin-4-yl)-ethanol, compound of formula 8 is reacted with dimethyl sulfoxide and oxalyl chloride in presence of an organic base, to obtain (1-Methyl- piperidin-4-yl) acetaldehyde, compound of formula 3. The organic base may be selected from triethylamine, tri n-propylamine, tri n-butylamine, tri-n-pentylamine or diisopropyl ethyl amine. Triethylamine is preferred as the organic base. The reaction may be carried out at -70 to -5O⁰C, preferably -65 to -60⁰C, in presence of dichloromethane. This reaction is known as Swern oxidation. The present invention intends to cover the variations of Swern oxidation within its scope.

The (l-Methyl-piperidin-4-yl) acetaldehyde, a compound of formula 3, thus obtained is. reacted with a hydrazine compound of formula 2 as discussed above to obtain N-methyl- 2-[3-(l-methyl-4-piperidyl)-li/-indol-5-yl]-ethanesulfonamide, compound of formula 1 or its salt

The present invention also provides a process for preparing compound of formula 7 comprising (a) reacting a compound of formula 4

Formula 4

with a compound of formula 5,

Formula 5 in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain a compound of formula 6

Formula 6 wherein each R₁ in Formula 5 and Formula 6 is independently selected from C₁-C₅ alkyl.

(b) catalytically hydrogenating the compound of formula 6 under atmospheric conditions to obtain a compound of formula 7

Form ula 7 wherein R₁ has the meaning as defined above.

Step a involves reaction of N-methyl piperidin-4-one, compound of formula 4 with a phosphonate ester, compound of formula 5, in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain an olefinic ester, a compound of formula 6.

The alkali metal hydroxide may be selected from potassium hydroxide, sodium hydroxide, cesium hydroxide, barium hydroxide, lithium hydroxide or tetrabutylammonium hydroxide and the like. The preferred alkali metal hydroxide is potassium hydroxide.

The alkali carbonate may be selected from sodium carbonate, potassium carbonate, lithium carbonate and the like. The preferred alkali carbonate is potassium carbonate. The reaction may also be carried out in the presence of mixtures of an alkali metal hydroxide and an alkali metal carbonate, for example, in presence of mixture of potassium hydroxide and potassium carbonate.

Further, the reaction may be advantageously carried out in presence of an organic solvent in anhydrous conditions at about 60-65⁰C. Reaction temperature preferably should not exceed 7O⁰C. A suitable organic solvent for the reaction may be selected from a polar to moderately polar or non-polar aprotic organic solvent. The solvent may be selected from a sulfoxide like dimethylsulfoxide; an amide like dimethylacetamide or dimethylformamide; a nitrile like acetonitrile, benzonitrile, an ether like diethylether or tetrahydrofuran, an aromatic or aliphatic hydrocarbon like toluene, chlorobenzene, heptane, hexane, etc.

Preferably the organic solvent is an aprotic non-polar organic solvent. More preferably, the aprotic non-polar organic solvent is toluene.

Suitable phosphonate esters which may be used according to the present invention are compounds of formula 5 wherein each R₁ is independently selected from Ci-C₅ alkyl. For example, each R₁ may be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. Accordingly, a suitable phosphonate ester may be triethyl phosphonoacetate, ethyl dimethyl phosphonoacetate or the like. The prefered phosphonate ester is triethyl phosphonoacetate.

The suitable phosphonate ester, a compound of formula 5, may be prepared from a trialkyl phosphite and a halo alkylester. For instance, triethyl phosphonoacetate may be prepared by reacting triethyl phosphite with ethyl bromoacetate. The reaction may be carried out with or without a solvent at a temperature ranging from 70-95 ⁰C. Preferably, the reaction is carried out without a solvent at a temperature of 90-95 ⁰C.

Step b involves hydrogenation of the olefinic ester of formula 6 obtained in step a above, to obtain a saturated ester derivative i.e. the compound of formula 7. The reaction may be carried out in presence of a metal catalyst and hydrogen gas in a suitable organic solvent. Further, the reaction is preferably carried out in the absence of any mineral or organic acid.

A metal catalyst may be selected from the group of noble metal catalysts like palladium, platinum, rhodium etc. Preferably the metal catalyst is palladium supported on Carbon. Preferred grade of Pd/C being 39-C supplied by M/s Arora -Matthey (India). The reaction may be carried out by purging hydrogen gas to the reaction mixture containing the metal catalyst and the compound of formula 6, at atmospheric pressure or preferably at very low pressure of upto 1 Kg/cm².

The reaction may be carried out at a temperature ranging from 15-4O⁰C. The reaction may be carried out in presence of a suitable organic solvent selected from group of alkanols like methanol, ethanol, isopropanol or n-butanol. The prefered solvent is Methanol.

The processes of the present invention for preparation of compound of formula 1 or salts thereof, from compound of formula 4 is illustrated in Schemes III and IV. The processes as summarized above and as outlined in Scheme III and IV, involve the steps a, b and e which are common for both the processes and hence each of these steps are described herein in context to both the schemes III and IV.

SCHEME HI & IV

form u Ia 4 fo rm u Ia 6 fo rm u Ia 7 form u Ia 8

fo rm u Ia 2

The following examples illustrate the process of the present invention which should not be construed as constituting a limitation thereto.

Example 1

Preparation of (l-Methyl-piperidin-4-ylidene)-acetic acid ethyl ester (a) Preparation of (Diethoxyphosphoryl)-acetic acid ethyl ester

To a 3-neck RBF, triethyl phosphate (99.7g, 0.59moles) was added, and the flask was gradually heated to 65-70⁰C under stirring. Ethyl bromoacetate (66.6ml, 0.59moles) was added to the flask in a drop- wise manner maintaining the temperature of the reaction mixture between 65-95 C. The reaction mixture was then heated to 70-75 C and maintained at this temperature for 2 to 3 hr. After the completion of the reaction, the mixture was allowed to cool to 45-50°C and degassed. The yield obtained is 100 %.

(b) Preparation of (l-Methyl-piperidin-4-ylidene)-acetic acid ethyl ester

Toluene (900ml) was added to a 3-neck RBF equipped with an overhead stirrer, powder funnel and stirrer. Sodium sulfate (Anhydrous) (134g), Potassium carbonate (83g, 0.600) and (diethoxy-phosphoryl)-acetic acid ethyl ester (134g, 0.59moles ) (as prepared above in example Ia) were gradually added in a series to the flask to form a suspension. 1 -Methyl piperidin-4-one(68g, 0.600moles) in 44OmL Toluene. (80g, 1.42moles) was added to the suspension, followed by addition of potassium hydroxide (pellets, 85%). The reaction mixture was stirred and was maintained with stirring for 30min, maintaining the temperature of the reaction below 70°C. The reaction was quenched by addition of solution of sodium bisulphite (15.5g) in 1300ml DM water. The toluene layer was separated and washed with 130OmL sodium bisulphite solution, DM water (2x134OmL) and warm water (2x134OmL). Toluene was distilled out at a temperature of 35-45°C under vacuum. The syrup obtained was degassed for 1-2 hrs to obtain the product as pale yellow colored syrup Yield 52.9% Example 2 Preparation of (l-MethyI-piperidin-4-yl)-acetic acid ethyl ester

To a 3 -neck RBF equipped over magnetic stirrer, powder funnel, hydrogen bubbler and thermometer pocket, was added (l-Methyl-piperidin-4-ylidene)-acetic acid ethyl ester

(10Og, 0.54moles) (prepared in example 1 above) and 100OmL of methanol. The flask was stirred at 25-30 C to obtain clear solution. 1Og of palladium suspended in 1OmL of DM water was added to the clear solution and the flask was purged with nitrogen and then with hydrogen gas at 25-30°C. The flask was maintained at 25-30°C with continuous bubbling of hydrogen gas at atmospheric pressure for 3-5 hrs. After completion of the reaction, the reaction mixture was filtered and the methanolic solution was collected. The methanolic solution was distilled at 35-45°C under vacuum, followed by co-distillation with toluene.

The syrup obtained was degassed for 1.0-2.0hr under vacuum at 35-45°C to yield product as pale yellow syrup. Yield- 95.4%

Example 3 Preparation of 2-(l-Methyl-piperidin-4-yl)-ethanol

(l-Methyl-piperidin-4-yl)-acetic acid ethyl ester (10Og, 0.54moles) in 60OmL of tetrahydrofuran was stirred under nitrogen atmosphere to obtain a clear solution. The solution was cooled to 10-15 ⁰C and vitride solution (67OmL, 65% solution in toluene) was added to it with stirring, maintaining temperature of the reaction mixture below 3O⁰C.

The reaction mixture was maintained with stirring at 25-3O⁰C for 3-4 hrs. After completion of reaction, the flask was cooled to 10-15⁰C and sodium hydroxide solution (10% solution in DM water) was added to the reaction mixture at a temperature below

3O⁰C. the flask was maintained with stirring for 30min.to the flask, toluene (800ml) was added and stirring was continued for another 30min. The layers were separated and the toluene layer collected was distilled under vacuum. The syrup obtained was degassed for l-2hr under vacuum at 35-45°C to obtain product as pale yellow colored syrup. Yield: 90 % Example 4 Preparation of (l-Methyl-piperidin-4-yl)-acetaldehyde

Dimethylsulfoxide (12Og, 1.68moles) was charged to dichloromethane (550OmL) in a RBF and stirred to obtain a clear solution. The solution was cooled to -60 to -65 °C and oxalyl chloride (8OmL, 0.84 moles) was added gradually to the above solution maintained at a temperature below -60 °C. A solution of 2-(l-Methyl-piperidin-4-yl)-ethanol (10Og, 0.69moles) (prepared above in example 3) in dichloromethane (150OmL) was added to the reaction mixture, gradually over a period of about lhr. The reaction mixture was maintained with stirring at -60 to -65 °C for 25-30min. Triethylamine (50OmL, 3.58moles) was added to the reaction flask and the reaction mixture was stirred for 15-20min. The temperature was gradually raised to 20-25°C and reaction mixture was stirred for 2 hrs. The reaction was quenched by addition of DM water (50OmL) and the flask was maintained with stirring for 30 min. the layers were separated and the dichloromethane layer was collected. The dicholoromethane layer was distilled out under reduced pressure top obtain a syrup which was degassed for 1-2 hrs to obtain the product as pale yellow syrup. Yield-51%

Example 5

Preparation of (l-MethyI-piperidin-4-yl)-acetaldehyde

(a) Preparation of Sodium diisobutyl-t-butoxyaluminium hydride reagent:

To a 3.01it 3-neck RB flask assembly equipped with overhead stirrer, powder funnel, nitrogen bubbler and thermometer pocket, sodium-terf-butoxide (80g, 0.83moles) and tetrahydrofuran (40OmL) was added under nitrogen pressure. The suspension obtained was cooled to -5 to O⁰C and DIBAH (20% solution in toluene, 68OmL) was added to it maintaining the temperature between -5 to O⁰C. The temperature of the reaction mixture was allowed to increase gradually to 20-25⁰C and it was maintained at this temperature with stirring for 2hrs. (b) To a 3 -neck RB flask assembly equipped with overhead stirrer, powder funnel, nitrogen bubbler and thermometer pocket, (l-Methyl-piperidin-4-yl)-acetic acid ethyl ester (10Og, 0.54moles) and tetrahydrofuran (40OmL) was added at 25-3O⁰C to obtain a solution. The reaction mixture was cooled to -5 to O⁰C and sodium diisobutyl-t- butoxyaluminium hydride reagent (as prepared in step 6a above) was added to it, maintaining the temperature of the reaction mixture between -5 to O⁰C. The reaction mixture was maintained at -5 to O⁰C under nitrogen pressure for 2-3hrs. After completion of the reaction, the reaction was quenched by addition of methanol (80ml) maintaining the temperature between -5 to O⁰C. The flask was stirred for 10-15 min at -5 to O⁰C. D M water (40OmL) was added to the reaction mixture maintaining the temperature below 2O⁰C. The product was extracted from the quenched reaction mixture using toluene (2x100OmL). The toluene layer was cooled, dried using anhydrous sodium sulphate and was distilled off completely under vacuum. The product obtained was degassed for 1-2 hr to yield the product as pale yellow syrup. Yield-75%

Example 6 Preparation ofN-methyl-2-[3-(l-methyl-4-piperidyl)-l/-T-indol-5-yl]- ethanesulfonamide hydrochloride (Naratriptan hydrochloride) A solution of 2-(l-Methylpiperidin-4-yl)-acetaldehyde(100gm) and Ethanol(500ml)was mixed with 2-(4-Hydrazino-phenyl) ethane sulfonic acid methyl-amide hydrochloride (160 gm) and stirred at 25-3O⁰C. Hydrochloric acid (100ml) and Acetic acid(lθθml) were added to the mixture and stirred at 25-3O⁰C. The mixture was gradually heated to 60-65⁰C and stirred for 12-16 hour at that temperature. The reaction mixture was cooled to 25-3O⁰C and water (20 VoI) was added with continued stirring. The stirred solution was basified with Caustic lye solution (400ml) and the product was extracted into dichloromethane. The organic layer was dried over Sodium sulfate and distilled out under vacuum to obtain syrup. The syrup was solubilised in Ethanol(5 Vol. wrt Naratriptan base syrup) and hydrochloric acid was added. The solution was stirred at 25-3O⁰C for 10-12 hrs to obtain solid. Yield 66%.

Claims

We claim

1. A process for preparing N-methyl-2-[3-(l-methyl-4-piperidyl)-lH-indol-5-yl]- ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1 comprising the steps of :

^■y Q Formula 7 Formula 3 wherein R₁ is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl and (b) reacting the compound of formula 3, with a compound of formula 2

15

2. The process as claimed in claim 1 wherein the reaction of compound of formula 3 with the compound of formula 2, is carried out at a temperature of 50⁰C to 80⁰C for a period of 10-15 hours at pH <2, under non-anhydrous conditions.

3. The process as claimed in claim 1 wherein the alkali metal alkoxide used in step a, is selected from sodium f-butoxide or potassium-/ butoxide.

4. A process for preparing N-methyl-2-[3-(l -methyl-4-piperidyl)-lH-indol-5-yl]-_/ ethanesulfonamide, a compound of formula 1 or its acid addition salts.

Formula 1 comprising the steps of :

Formula 7 Formula 8 wherein Rj is independently selected from Ci-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

(b) reacting the compound of formula 8, with dimethyl sulfoxide and oxalyl chloride in presence of an organic base to obtain a compound of formula 3 , and

Formula 3 (c) reacting the compound of formula 3 with a compound of formula 2

5. The process as claimed in claim 4 wherein the organic base in step b is selected from a group consisting of triethylamine, tri n-propylamine, tri n-butylamine, tri-n-pentylamine and diisopropyl ethyl amine.

6. The process as claimed in claim 4 wherein the reaction of compound of formula 3 with compound of formula 2, is carried out at a temperature of 50⁰C to 80⁰C for a period of 10-15 hours at pH <2, under non-anhydrous conditions.

7. A process for preparing the compound of formula 7

Formula 7 comprising the steps of : (a) reacting a compound of formula 4

Formula 4 with a compound of formula 5

(b) hydrogenating the compound of formula 6 obtained in step (a) above, to obtain a compound of formula 7, wherein R) has the meaning as defined above.

8. The process as claimed in claim 7, wherein the phosphonate ester is selected from a group consisting of triethyl phosphonoacetate, ethyl dimethyl phosphonoacetate and ethyl diphenyl phosphonoacetate.

9. The process as claimed in claim 7, wherein the phosphonate ester is triethyl phosphonoacetate.

10. The process as claimed in claim 7, wherein alkali metal hydroxide is selected from a group consisting of potassium hydroxide, sodium hydroxide, cesium hydroxide, barium hydroxide and lithium hydroxide.

11. The process as claimed in claim 7, wherein the alkali metal carbonate is selected from a group consisting of potassium carbonate, sodium carbonate and lithium carbonate.

12. The process as claimed in claim 7 wherein step a is carried out in presence potassium hydroxide and potassium carbonate.

13. The process as claimed in claim 7, wherein the hydrogenation is carried out at atmospheric pressure.

14. A process for preparing, l-methyl-piperidin-4-yl-acetaldehyde, a compound of formula 3

Formula 7 Formula 3 comprising reacting a compound of formula 7, wherein R₁ is independently selected from C₁-C₅ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. with sodium diisobutyl-t- butoxyaluminium hydride reagent in presence of an alkali metal alkoxide.